Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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  • See Evidence submitted by expert panel for details.

Variant: NM_000277.3(PAH):c.1065+1G>T

CA312806

203872 (ClinVar)

Gene: PAH
Condition: phenylketonuria
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 954bf65c-2e5b-43f0-b432-bd27842a32f9

HGVS expressions

NM_000277.3:c.1065+1G>T
NM_000277.3(PAH):c.1065+1G>T
NC_000012.12:g.102844335C>A
CM000674.2:g.102844335C>A
NC_000012.11:g.103238113C>A
CM000674.1:g.103238113C>A
NC_000012.10:g.101762243C>A
NG_008690.1:g.78268G>T
NG_008690.2:g.119076G>T
NM_000277.1:c.1065+1G>T
NM_000277.2:c.1065+1G>T
NM_001354304.1:c.1065+1G>T
NM_001354304.2:c.1065+1G>T
ENST00000307000.7:c.1050+1G>T
ENST00000549247.6:n.824+1G>T
ENST00000551114.2:n.727+1G>T
ENST00000553106.5:c.1065+1G>T
ENST00000635477.1:n.169+1G>T
ENST00000635528.1:n.580+1G>T

Likely Pathogenic

Met criteria codes 4
PP4 PM2 PM3_Supporting PVS1_Strong

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Phenylketonuria VCEP
This c.1065+1G>T variant in PAH was reported in 1 patient with moderate PKU (PMID: 18299955) detected with the pathogenic variant p.Leu48Ser. A defect in BH4 metabolism was not excluded. This variant is absent from population databases. This variant in the +1 splice donor site results in exon skipping. The variant does not disrupt the reading frame, but the altered region is critical to protein function. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1_strong, PM2, PP4, PM3_supporting.
Met criteria codes
PP4
PP4_met: This variant was documented in 1 patient with moderate PKU (PMID: 18299955). 18299955, Bercovich - This variant was documented in 1 patient with moderate PKU. The paper defined moderate PKU as plasma phenylalanine concentrations of 10–20 mg/dl. A defect in BH4 metabolism was not excluded through a BH4 loading test, urinary pterin analysis and DHPR activity assay.
PubMed:18299955
PM2
PM2_met: This variant is absent from population databases gnomAD and ExAC.
PM3_Supporting
PM3_supporting: This variant was detected in trans with a pathogenic variant in 1 patient with moderate PKU (PMID: 18299955). FYI, there is a paper in Chinese that mentions this variant, but it is unclear if there is genotype info available in the paper (PMID: 22161097). 18299955, Bercovich - This variant was detected in trans with the pathogenic PAH variant p.Leu48Ser in 1 patient with moderate PKU. Parental analysis was not performed to confirm compound heterozygosity.
PVS1_Strong
PVS1_strong: This variant in the +1 splice donor site of IVS10 results in exon skipping or use of a cryptic splice site. The variant does not disrupt the reading frame and nonsense mediated decay (NMD) is not predicted to occur. The truncated/altered region is critical to protein function. This variant breaks the splice site in IVS10 according to Splice AI (0.6 - splice-altering) and TraP (0.909, >99%ile, probably damaging).
Approved on: 2020-10-19
Published on: 2020-10-19
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